tbuckley/cabot-search huggingface dataset:
Selective Cell Size MRI Differentiates Brain Tumors from Radiation Necrosis
Authors: Sean P. Devan, Xiaoyu Jiang, Guozhen Luo, Jingping Xie, James D. Quirk, John A. Engelbach, Hannah Harmsen, Eliot T. McKinley, Jing Cui, Zhongliang Zu, Albert Attia, Joel R. Garbow, John C. Gore, Colin D. McKnight, Austin N. Kirschner, Junzhong Xu
Journal: Cancer Research (2022)

Abstract Brain metastasis is a common characteristic of late-stage lung cancers. High doses of targeted radiotherapy can control tumor growth in the brain but can also result in radiotherapy-induced necrosis. Current methods are limited for distinguishing whether new parenchymal lesions following radiotherapy are recurrent tumors or radiotherapy-induced necrosis, but the clinical management of these two classes of lesions differs significantly. Here, we developed, validated, and evaluated a new MRI technique termed selective size imaging using filters via diffusion times (SSIFT) to differentiate brain tumors from radiotherapy necrosis in the brain. This approach generates a signal filter that leverages diffusion time dependence to establish a cell size–weighted map. Computer simulations in silico, cultured cancer cells in vitro, and animals with brain tumors in vivo were used to comprehensively validate the specificity of SSIFT for detecting typical large cancer cells and the ability to differentiate brain tumors from radiotherapy necrosis. SSIFT was also implemented in patients with metastatic brain cancer and radiotherapy necrosis. SSIFT showed high correlation with mean cell sizes in the relevant range of less than 20 μm. The specificity of SSIFT for brain tumors and reduced contrast in other brain etiologies allowed SSIFT to differentiate brain tumors from peritumoral edema and radiotherapy necrosis. In conclusion, this new, cell size–based MRI method provides a unique contrast to differentiate brain tumors from other pathologies in the brain. Significance: This work introduces and provides preclinical validation of a new diffusion MRI method that exploits intrinsic differences in cell sizes to distinguish brain tumors and radiotherapy necrosis.
Inhibition of astrocytic DRD2 suppresses CNS inflammation in an animal model of multiple sclerosis
Authors: Shen-zhao Lu, Yue Wu, Yong-shun Guo, Pei-zhou Liang, Shu Yin, Yan-qing Yin, Xiu-li Zhang, Yan-Fang Liu, Hong-yan Wang, Yi-chuan Xiao, Xin-miao Liang, Jia-wei Zhou
Journal: The Journal of Experimental Medicine (2022)

Astrocyte activation is associated with progressive inflammatory demyelination in multiple sclerosis (MS). The molecular mechanisms underlying astrocyte activation remain incompletely understood. Recent studies have suggested that classical neurotransmitter receptors are implicated in the modulation of brain innate immunity. We investigated the role of dopamine signaling in the process of astrocyte activation. Here, we show the upregulation of dopamine D2 receptor (DRD2) in reactive astrocytes in MS brain and noncanonical role of astrocytic DRD2 in MS pathogenesis. Mice deficient in astrocytic Drd2 exhibit a remarkable suppression of reactive astrocytes and amelioration of experimental autoimmune encephalomyelitis (EAE). Mechanistically, DRD2 regulates the expression of 6-pyruvoyl-tetrahydropterin synthase, which modulates NF-κB activity through protein kinase C-δ. Pharmacological blockade of astrocytic DRD2 with a DRD2 antagonist dehydrocorybulbine remarkably inhibits the inflammatory response in mice lacking neuronal Drd2. Together, our findings reveal previously an uncharted role for DRD2 in astrocyte activation during EAE-associated CNS inflammation. Its therapeutic inhibition may provide a potent lever to alleviate autoimmune diseases.
Symptoms and risk factors for long COVID in non-hospitalized adults
Authors: Anuradhaa Subramanian, Krishnarajah Nirantharakumar, Sarah Hughes, Puja Myles, Tim Williams, Krishna M. Gokhale, Tom Taverner, Joht Singh Chandan, Kirsty Brown, Nikita Simms-Williams, Anoop D. Shah, Megha Singh, Farah Kidy, Kelvin Okoth, Richard Hotham, Nasir Bashir, Neil Cockburn, Siang Ing Lee, Grace M. Turner, Georgios V. Gkoutos, Olalekan Lee Aiyegbusi, Christel McMullan, Alastair K. Denniston, Elizabeth Sapey, Janet M. Lord, David C. Wraith, Edward Leggett, Clare Iles, Tom Marshall, Malcolm J. Price, Steven Marwaha, Elin Haf Davies, Louise J. Jackson, Karen L. Matthews, Jenny Camaradou, Melanie Calvert, Shamil Haroon
Journal: Nature Medicine (2022)

Abstract Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02–8.39), hair loss (3.99, 3.63–4.39), sneezing (2.77, 1.40–5.50), ejaculation difficulty (2.63, 1.61–4.28) and reduced libido (2.36, 1.61–3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.
The function of Wtap in N6-adenosine methylation of mRNAs controls T cell receptor signaling and survival of T cells
Authors: Taku Ito-Kureha, Cristina Leoni, Kayla Borland, Giulia Cantini, Marian Bataclan, Rebecca N. Metzger, Gregor Ammann, Anne B. Krug, Annalisa Marsico, Stefanie Kaiser, Stefan Canzar, Stefan Feske, Silvia Monticelli, Julian König, Vigo Heissmeyer
Journal: Nature Immunology (2022)
Bidirectional genome-wide CRISPR screens reveal host factors regulating SARS-CoV-2, MERS-CoV and seasonal HCoVs
Authors: Antoine Rebendenne, Priyanka Roy, Boris Bonaventure, Ana Luiza Chaves Valadão, Lowiese Desmarets, Mary Arnaud-Arnould, Yves Rouillé, Marine Tauziet, Donatella Giovannini, Jawida Touhami, Yenarae Lee, Peter DeWeirdt, Mudra Hegde, Serge Urbach, Khadija El Koulali, Francisco Garcia de Gracia, Joe McKellar, Jean Dubuisson, Mélanie Wencker, Sandrine Belouzard, Olivier Moncorgé, John G. Doench, Caroline Goujon
Journal: Nature Genetics (2022)
Genome-wide bidirectional CRISPR screens identify mucins as host factors modulating SARS-CoV-2 infection
Authors: Scott B. Biering, Sylvia A. Sarnik, Eleanor Wang, James R. Zengel, Sarah R. Leist, Alexandra Schäfer, Varun Sathyan, Padraig Hawkins, Kenichi Okuda, Cyrus Tau, Aditya R. Jangid, Connor V. Duffy, Jin Wei, Rodney C. Gilmore, Mia Madel Alfajaro, Madison S. Strine, Xammy Nguyenla, Erik Van Dis, Carmelle Catamura, Livia H. Yamashiro, Julia A. Belk, Adam Begeman, Jessica C. Stark, D. Judy Shon, Douglas M. Fox, Shahrzad Ezzatpour, Emily Huang, Nico Olegario, Arjun Rustagi, Allison S. Volmer, Alessandra Livraghi-Butrico, Eddie Wehri, Richard R. Behringer, Dong-Joo Cheon, Julia Schaletzky, Hector C. Aguilar, Andreas S. Puschnik, Brian Button, Benjamin A. Pinsky, Catherine A. Blish, Ralph S. Baric, Wanda K. O’Neal, Carolyn R. Bertozzi, Craig B. Wilen, Richard C. Boucher, Jan E. Carette, Sarah A. Stanley, Eva Harris, Silvana Konermann, Patrick D. Hsu
Journal: Nature Genetics (2022)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a range of symptoms in infected individuals, from mild respiratory illness to acute respiratory distress syndrome. A systematic understanding of host factors influencing viral infection is critical to elucidate SARS-CoV-2-host interactions and the progression of Coronavirus disease 2019 (COVID-19). Here, we conducted genome-wide CRISPR knockout and activation screens in human lung epithelial cells with endogenous expression of the SARS-CoV-2 entry factors ACE2 and TMPRSS2. We uncovered proviral and antiviral factors across highly interconnected host pathways, including clathrin transport, inflammatory signaling, cell-cycle regulation, and transcriptional and epigenetic regulation. We further identified mucins, a family of high molecular weight glycoproteins, as a prominent viral restriction network that inhibits SARS-CoV-2 infection in vitro and in murine models. These mucins also inhibit infection of diverse respiratory viruses. This functional landscape of SARS-CoV-2 host factors provides a physiologically relevant starting point for new host-directed therapeutics and highlights airway mucins as a host defense mechanism.
Mechanoregulation of Metastasis beyond the Matrix
Authors: Ekrem Emrah Er, Maria Tello-Lafoz, Morgan Huse
Journal: Cancer Research (2022)

Epithelial transformation and carcinogenesis are characterized by profound alterations in cell mechanics that significantly affect multiple steps of the metastatic cascade. The ability of cancer cells to grow in the primary tumor, to locally invade through the confining extracellular matrix, to survive in circulation, and to extravasate into distant vital organs all depend on specific mechanical characteristics. Importantly, recent studies have shown that the mechanical properties of cancer cells also influence their interactions with immune and stromal cells. Here, we discuss the mechanical changes that cancer cells undergo during metastasis, how these changes affect immune and stromal responses, and the implications of these new insights for therapeutic intervention.
Effect of a bacteriocin-producing <i>Streptococcus salivarius</i> on the pathogen <i>Fusobacterium nucleatum</i> in a model of the human distal colon
Authors: Garreth W. Lawrence, Niamh McCarthy, Calum J. Walsh, Tais M. Kunyoshi, Elaine M. Lawton, Paula M. O’Connor, Máire Begley, Paul D. Cotter, Caitriona M. Guinane
Journal: Gut Microbes (2022)

The gut microbiome is a vast reservoir of microbes, some of which produce antimicrobial peptides called bacteriocins that may inhibit specific bacteria associated with disease. Fusobacterium nucleatum is an emerging human bacterial pathogen associated with gastrointestinal diseases including colorectal cancer (CRC). In this study, fecal samples of healthy donors were screened for potential bacteriocin-producing probiotics with antimicrobial activity against F. nucleatum. A novel isolate, designated as Streptococcus salivarius DPC6993 demonstrated a narrow-spectrum of antimicrobial activity against F. nucleatum in vitro. In silico analysis of the S. salivarius DPC6993 genome revealed the presence of genes involved in the production of the bacteriocins salivaricin A5 and salivaricin B. After 6 h in a colon fermentation model, there was a significant drop in the number of F. nucleatum in samples that had been simultaneously inoculated with S. salivarius DPC6993 + F. nucleatum DSM15643 compared to those inoculated with F. nucleatum DSM15643 alone (mean ± SD: 9243.3 ± 3408.4 vs 29688.9 ± 4993.9 copies/μl). Furthermore, 16S rRNA amplicon analysis revealed a significant difference in the mean relative abundances of Fusobacterium between samples inoculated with both S. salivarius DPC6993 and F. nucleatum DSM15643 (0.05%) and F. nucleatum DSM15643 only (0.32%). Diversity analysis indicated minimal impact exerted by S. salivarius DPC6993 on the surrounding microbiota. Overall, this study highlights the ability of a natural gut bacterium to target a bacterial pathogen associated with CRC. The specific targeting of CRC-associated pathogens by biotherapeutics may ultimately reduce the risk of CRC development and positively impact CRC outcomes.
Implementation research on noncommunicable disease prevention and control interventions in low- and middle-income countries: A systematic review
Authors: Celestin Hategeka, Prince Adu, Allissa Desloge, Robert Marten, Ruitai Shao, Maoyi Tian, Ting Wei, Margaret E. Kruk
Journal: PLoS Medicine (2022)

While the evidence for the clinical effectiveness of most noncommunicable disease (NCD) prevention and treatment interventions is well established, care delivery models and means of scaling these up in a variety of resource-constrained health systems are not. The objective of this review was to synthesize evidence on the current state of implementation research on priority NCD prevention and control interventions provided by health systems in low- and middle-income countries (LMICs).
Deactylation by SIRT1 enables liquid–liquid phase separation of IRF3/IRF7 in innate antiviral immunity
Authors: Ziran Qin, Xiuwu Fang, Wenhuan Sun, Zhenyu Ma, Tong Dai, Shuai Wang, Zhi Zong, Huizhe Huang, Heng Ru, Huasong Lu, Bing Yang, Shixian Lin, Fangfang Zhou, Long Zhang
Journal: Nature Immunology (2022)
Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex
Authors: Emma Gerrits, Lucia A. A. Giannini, Nieske Brouwer, Shamiram Melhem, Danielle Seilhean, Isabelle Le Ber, Alwin Kamermans, Gijs Kooij, Helga E. de Vries, Erik W. G. M. Boddeke, Harro Seelaar, John C. van Swieten, Bart J. L. Eggen
Journal: Nature Neuroscience (2022)
Effect of Empagliflozin on Kidney Biochemical and Imaging Outcomes in Patients With Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)
Authors: Matthew M.Y. Lee, Keith A. Gillis, Katriona J.M. Brooksbank, Sarah Allwood-Spiers, Pauline Hall Barrientos, Kirsty Wetherall, Giles Roditi, Bashair AlHummiany, Colin Berry, Ross T. Campbell, Victor Chong, Liz Coyle, Kieran F. Docherty, John G. Dreisbach, Bernd Kuehn, Catherine Labinjoh, Ninian N. Lang, Vera Lennie, Kenneth Mangion, Alex McConnachie, Clare L. Murphy, Colin J. Petrie, John R. Petrie, Kanishka Sharma, Steven Sourbron, Iain A. Speirits, Joyce Thompson, Paul Welsh, Rosemary Woodward, Ann Wright, Aleksandra Radjenovic, John J.V. McMurray, Pardeep S. Jhund, Mark C. Petrie, Naveed Sattar, Patrick B. Mark
Journal: Circulation (2022)
Management of Atrial Fibrillation Across the Spectrum of Heart Failure With Preserved and Reduced Ejection Fraction
Authors: Yogesh N.V. Reddy, Barry A. Borlaug, Bernard J. Gersh
Journal: Circulation (2022)

Atrial fibrillation (AF) is the most common arrhythmia among patients with heart failure (HF), and HF is the most common cause of death for patients presenting with clinical AF. AF is frequently associated with pathological atrial myocardial dysfunction and remodeling, a triad that has been called atrial myopathy. AF can be the cause or consequence of clinical HF, and the directionality varies between individual patients and across the spectrum of HF. Although initial trials suggested no advantage for a systematic rhythm control strategy in HF with reduced ejection fraction, recent data suggest that select patients may benefit from attempts to maintain sinus rhythm with catheter ablation. Preliminary data also show a close relationship among AF, left atrial myopathy, mitral regurgitation, and HF with preserved ejection, with potential clinical benefits to catheter ablation therapy. The modern management of AF in HF also requires consideration of the degree of atrial myopathy and chronicity of AF, in addition to the pathogenesis and phenotype of the underlying left ventricular HF. In this review, we summarize the contemporary management of AF and provide practical guidance and areas in need of future investigation.
Response by van der Stuijt et al to Letter Regarding Article, “Efficacy and Safety of Appropriate Shocks and Antitachycardia Pacing in Transvenous and Subcutaneous Implantable Defibrillators: Analysis of All Appropriate Therapy in the PRAETORIAN Trial”
Authors: Willeke van der Stuijt, Lonneke Smeding, Louise R.A. Olde Nordkamp, Reinoud E. Knops
Journal: Circulation (2022)
SARS-CoV-2 Omicron escapes mRNA vaccine booster-induced antibody neutralisation in patients with autoimmune rheumatic diseases: an observational cohort study
Authors: Woo-Joong Kim, Seong-Ho Choi, Ji Young Park, Jung Soo Song, Jin-Won Chung, Sang Tae Choi
Journal: Annals of the Rheumatic Diseases (2022)

Objectives This study investigates whether COVID-19 vaccines can elicit cross-reactive antibody responses against the Omicron variant in patients with autoimmune rheumatic diseases (ARDs). Methods This observational cohort study comprised 149 patients with ARDs and 94 healthcare workers (HCWs). Blood samples were obtained at enrolment, a median of 15 weeks after the second vaccine dose or 8 weeks after the third dose. The functional cross-neutralisation capacity of sera was measured using the Omicron variant receptor-binding domain-ACE2 binding inhibition assay. We assessed the incidence of breakthrough infections and the potential correlation with neutralising responses in participants after receiving third doses. The association of time-from-vaccine and neutralising responses in sera was predicted using linear regression analysis. Results The mean cross-neutralising responses against the Omicron variant developed after the second dose was 11.5% in patients with ARDs and 18.1% in HCWs (p=0.007). These responses were significantly lower in patients with ARDs than in HCWs after the third dose (26.8% vs 50.3%, p<0.0001). Only 39.2% of the patient sera showed functional neutralisation capacity to the Omicron variant and cross-neutralising responses were shown to be poorly correlated with anti-spike immunoglobulin G titres. Within 6 weeks of immunological assessments, significantly lower Omicron-neutralising responses were detected in sera from patients with ARDs who developed breakthrough infections compared with those who did not (p=0.018). Additionally, a relative decline was implied in neutralising responses against the Omicron variant as a reference to the wild-type virus during 120 days since the third vaccination, with a predicted decay rate of −0.351%/day (95% CI, −0.559 to −0.144, p=0.001). Conclusions Striking antibody evasion manifested by the Omicron variant in patients with ARDs and current vaccine-induced immunity may not confer broad protection from Omicron breakthrough infection, highlighting the need for further research on vaccine effectiveness in patients with immune dysfunctions. The data that support the findings of this study are available from the corresponding authors on reasonable request.
Old buildings and out of date facilities are costing the NHS dear
Authors: Saffron Cordery
Journal: BMJ (2022)

Amyotrophic lateral sclerosis (ALS) is a fatal neuromuscular disease characterized by motor neuron (MN) death. Lipid dysregulation manifests during disease; however, it is unclear whether lipid homeostasis is adversely affected in the in the spinal cord gray matter (GM), and if so, whether it is because of an aberrant increase in lipid synthesis. Moreover, it is unknown whether lipid dysregulation contributes to MN death. Here, we show that cholesterol ester (CE) and triacylglycerol levels are elevated several-fold in the spinal cord GM of male sporadic ALS patients. Interestingly, HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, was reduced in the spinal cord GM of ALS patients. Increased cytosolic phospholipase A2 activity and lyso-phosphatidylcholine (Lyso-PC) levels in ALS patients suggest that CE accumulation was driven by acyl group transfer from PC to cholesterol. Notably, Lyso-PC, a byproduct of CE synthesis, was toxic to human MNs <i>in vitro</i>. Elevations in CE, triacylglycerol, and Lyso-PC were also found in the spinal cord of SOD1<sup>G93A</sup> mice, a model of ALS. Similar to ALS patients, a compensatory downregulation of cholesterol synthesis occurred in the spinal cord of SOD1<sup>G93A</sup> mice; levels of sterol regulatory element binding protein 2, a transcriptional regulator of cholesterol synthesis, progressively declined. Remarkably, overexpressing sterol regulatory element binding protein 2 in the spinal cord of normal mice to model CE accumulation led to ALS-like lipid pathology, MN death, astrogliosis, paralysis, and reduced survival. Thus, spinal cord lipid dysregulation in ALS likely contributes to neurodegeneration and developing therapies to restore lipid homeostasis may lead to a treatment for ALS. <b>SIGNIFICANCE STATEMENT</b> Neurons that control muscular function progressively degenerate in patients with amyotrophic lateral sclerosis (ALS). Lipid dysregulation is a feature of ALS; however, it is unclear whether disrupted lipid homeostasis (i.e., lipid cacostasis) occurs proximal to degenerating neurons in the spinal cord, what causes it, and whether it contributes to neurodegeneration. Here we show that lipid cacostasis occurs in the spinal cord gray matter of ALS patients. Lipid accumulation was not associated with an aberrant increase in synthesis or reduced hydrolysis, as enzymatic and transcriptional regulators of lipid synthesis were downregulated during disease. Last, we demonstrated that genetic induction of lipid cacostasis in the CNS of normal mice was associated with ALS-like lipid pathology, astrogliosis, neurodegeneration, and clinical features of ALS.
Ready for impact? A validity and feasibility study of instrumented mouthguards (iMGs)
Authors: Ben Jones, James Tooby, Dan Weaving, Kevin Till, Cameron Owen, Mark Begonia, Keith A Stokes, Steven Rowson, Gemma Phillips, Sharief Hendricks, Éanna Cian Falvey, Marwan Al-Dawoud, Gregory Tierney
Journal: British Journal of Sports Medicine (2022)

Objectives Assess the validity and feasibility of current instrumented mouthguards (iMGs) and associated systems. Methods Phase I; four iMG systems (Biocore-Football Research Inc (FRI), HitIQ, ORB, Prevent) were compared against dummy headform laboratory criterion standards (25, 50, 75, 100 g ). Phase II; four iMG systems were evaluated for on-field validity of iMG-triggered events against video-verification to determine true-positives, false-positives and false-negatives (20±9 player matches per iMG). Phase III; four iMG systems were evaluated by 18 rugby players, for perceptions of fit , comfort and function . Phase IV; three iMG systems (Biocore-FRI, HitIQ, Prevent) were evaluated for practical feasibility (System Usability Scale (SUS)) by four practitioners. Results Phase I; total concordance correlation coefficients were 0.986, 0.965, 0.525 and 0.984 for Biocore-FRI, HitIQ, ORB and Prevent. Phase II; different on-field kinematics were observed between iMGs. Positive predictive values were 0.98, 0.90, 0.53 and 0.94 for Biocore-FRI, HitIQ, ORB and Prevent. Sensitivity values were 0.51, 0.40, 0.71 and 0.75 for Biocore-FRI, HitIQ, ORB and Prevent. Phase III; player perceptions of fit , comfort and function were 77%, 6/10, 55% for Biocore-FRI, 88%, 8/10, 61% for HitIQ, 65%, 5/10, 43% for ORB and 85%, 8/10, 67% for Prevent. Phase IV; SUS (preparation-management) was 51.3–50.6/100, 71.3–78.8/100 and 83.8–80.0/100 for Biocore-FRI, HitIQ and Prevent. Conclusion This study shows differences between current iMG systems exist. Sporting organisations can use these findings when evaluating which iMG system is most appropriate to monitor head acceleration events in athletes, supporting player welfare initiatives related to concussion and head acceleration exposure.